Individual gene disruptions from balanced chromosomal rearrangements define novel neurodevelopmental loci and genomic disorders. H. Brand1,4, V. Pillalamarri1, I. Blumenthal1, M. Stone1, S. Pereira2, C. Morton2,3,4, J. Gusella1,4,5, M. Talkowski1,4,5 1) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 2) Departments of Obstetrics, Gynecology, and Reproductive Biology , Brigham and Womens Hospital and Harvard Medical School, Boston, MA; 3) Department of Pathology, Brigham and Womens Hospital and Harvard Medical School, Boston, MA; 4) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; 5) Departments of Psychiatry, Neurology, and Genetics, Harvard Medical School, Boston, MA.

   Cytogenetically defined balanced chromosomal aberrations (BCAs) represent substantial contributors to congenital anomalies but have been only routinely detected at extremely low resolution by karyotyping as deep, high resolution whole-genome sequencing (WGS) is cost prohibitive. Recent studies from our laboratory have delineated BCAs at high resolution using a large-insert WGS approach to derive nucleotide resolution of BCA breakpoints at a cost comparable to conventional cytogenetic methods. We previously reported sequencing of 38 subjects with a neurodevelopment disorder (NDD) and found several disruptions in novel genes with a strong effect on neurodevelopment (Talkowski et al., 2012, Cell). Herein we report sequencing 56 independent subjects with congenital anomalies harboring a karyotypically identified BCA. We discovered complex rearrangements (>3 breakpoints) in 15 subjects, representing ~10-fold increase over cytogenetic estimates. Of the 41 cases with canonical (non-complex) BCAs we found disruption of 27 genes among 26 subjects, many of which represent likely pathogenic loci. In DGAP055, sequencing identified disruption of CDK6, a locus within a 7q21 microdeletion syndrome associated with mental retardation, microcephaly, dysmorphism, and short stature; no causative gene has been identified. This disorder includes many symptoms overlapping with DGAP055s mental retardation, microcephaly, and short stature. Furthermore, CDK6 is a strong candidate for a causal role in short stature based on compelling evidence from GWAS association of CDK6 variants with height (rs2282978; p=7.8E-23). Two other genes (CACNA1C, CTNND2) demonstrate the variable expressivity of NDD even in known causal loci, as mutations in these genes cause Timothy syndrome and cri-du-chat syndrome, respectively, but neither of these subjects presented with hallmark symptoms of the respective disorder. Another intriguing class of loci involves genes disrupted in subjects with a complex NDD that are also associated with other psychiatric disorders: TRANK1 (bipolar disorder), DOCK9 (bipolar), TCF4 (schizophrenia), and ZNF804A (schizophrenia). This study emphasizes the significance of cytologically visible chromosomal abnormalities as a unique resource for defining strong effect mutations with a significant impact in human developmental disorders, and argues for widespread adoption of methods to delineate these events in routine genetic studies.

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